The nervous system includes the Central Nervous System (CNS) and the Peripheral Nervous System (PNS), the latter including the Somatic Nervous System (SNS) and Autonomic Nervous System (ANS). The CNS includes the brain and the spinal cord. The spinal cord is the main communication route for signals between the body and the brain. The SNS and ANS overlap the CNS and PNS. There are 31 pairs of spinal nerves arising from cervical (8), thoracic (12), lumbar (5), sacral (5) and coccygeal (1) segments. The spinal nerves contain both sensory and motor fibers. Efferent nerves (as opposed to afferent nerves) are the nerves leading from the central nervous system to an effector organ, and efferent neural signals refer to neural signals from the brain that are transmitted via spinal cord pathways to effector organs. Afferent nerves are the nerves leading to the central nervous system, and afferent neural signals refer to neural signals being transmitted to the brain.
The ANS consists of two divisions, the sympathetic nervous system and the parasympathetic nervous system, FIG. 1, and is responsible for regulating bodily functions including heart rate, respiration, digestion, bladder tone, sexual response and other functions. Activation of the sympathetic nervous system results in preparation of the body for stressful or emergency situations, while activation of the parasympathetic nervous system results in conservation and restoration and controls body processes during normal situations. For specific organs that are innervated by the autonomic nervous system, it is well known which spinal levels are involved. FIG. 2 shows segmental sympathetic and parasympathetic innervation of various organs. Parasympathetic innervation is either through the vagus nerve (cranial nerve X) or at the sacral levels (S2-S4). Sympathetic preganglionic neurons either synapse in the sympathetic chain ganglia or project through the sympathetic chain ganglia and synapse at various ganglia such as superior mesenteric ganglia or inferior mesenteric ganglia. The post-ganglionic neuron then projects to the end organ that it innervates. Parasympathetic pre-ganglionic neurons (from cranial nerve X and below) synapse very close to the organ they innervate and usually in a nerve plexus attached to the organ, and synapse with a post-ganglionic neuron that sends projections to the organ. The autonomic nervous system includes both sensory and motor neurons.
The ability to activate or inhibit either the sympathetic or parasympathetic nervous system would enable the regulation of numerous bodily functions and enable the treatment of specific disorders related to dysfunction of either the sympathetic or parasympathetic system. Normal functions that are potentially regulated by modulation of sympathetic or parasympathetic activity include modulating bronchodilation in the airways, modulating vasoconstriction in the skin and organs, stimulating gluconeogenesis and glucose release from the liver, stimulating secretion of epinephrine and norepinephrine by the adrenal gland, modulation of sweating, slowing or increasing heartrate and pumping efficiency, modulating tidal volume and rate of respiration, slowing or increasing intestinal processes involved with digestion, modulating urine production, modulating bladder contraction, modulating sphincter control, stimulating erection and sexual arousal, and numerous others. Beyond modulating normal functions, there are numerous disorders of the ANS that have been described and are referred to as dysautonomias, and is due to failure or disruption of either the sympathetic or parasympathetic divisions of the ANS. Specific such disorders include autoimmune autonomic ganglionopathy, congenital central hypoventilation syndrome, familiar dysautonomia, Holmes-Adie syndrome, multiple system atrophy, Shy-Drager syndrome, neurally mediated syncope, orthostatic hypotension, postural tachycardia syndrome, striatonigral degeneration and vasovagal syncope. Elevated sympathetic tone has been linked to disorders such as heart failure, hypertension, obesity, obstructive sleep apnea, diabetes, migraine, parkinsonian symptoms, septic shock, primary hyperhidrosis, complex regional pain syndrome and numerous others.
As there are many disorders and dysfunctions associated with abnormal regulation of autonomically-innervated effector organs, the ability to regulate the autonomic nervous system would enable important new therapeutic strategies. We have developed novel approaches to modulating the autonomic nervous system using various implementations of trans-spinal direct current stimulation (tsDCS).
The bladder is one example of an autonomically controlled organ. The bladder functions as a reservoir and is responsible for storing urine that has been formed by the kidneys in the process of eliminating metabolites and excess water from the blood. The stored urine is released via the urethra in the process of micturition.
The pathways mediating neural control of bladder function are well established and include sympathetic, parasympathetic and somatic pathways. Referring to FIG. 3, sympathetic control of the bladder is from sympathetic efferents from T11-L2 that run via the sympathetic trunk and the splanchnic nerves to the inferior mesenteric ganglion. Post-ganglionic fibers contribute to the hypogastric plexus and reach the bladder where they synapse on the detrusor muscle, and also synapse on the sphincter vesicae at the bladder neck. Parasympathetic control is from parasympathetic fibers that arise from S2-S4 and travel via the pelvic splanchnic nerves to synapse on post-ganglionic neurons located in a dense plexus among the detrusor smooth muscle cells in the wall of the bladder. Post-ganglionic parasympathetic fibers cause contraction of the bladder detrusor muscle and relaxation of the sphincter vesicae. The external urethral sphincter (EUS) consists of striated muscle and is under voluntary control via alpha motor neurons in Onuf's nucleus in the ventral horns of S2-S4. Afferent responses from bladder stretch receptors enter the spinal cord at T11-L2 and also S2-S4 where they travel up to brainstem areas. Sensory fibers in the urethral wall respond to urinary flow by causing firing of their cell bodies located in dorsal root ganglia, which synapse on neurons in the spinal cord dorsal horn. These sensory fibers travel to the spinal cord via the pudendal nerve, and transection of this sensory nerve reduces bladder contraction strength and voiding efficiency.
Urinary retention is an inability to empty the bladder completely and can be acute or chronic. Retention can be due to numerous issues, including constipation, prostatic enlargement, urethral strictures, urinary tract stones, tumors, and nerve conduction problems. Such nerve conduction problems are seen in brain and spinal cord injuries, diabetes, multiple sclerosis, stroke, pelvic surgery, heavy metal poisoning, aging and idiopathically. These result in either weak bladder contraction and/or excess sphincter activation. As such, modulation strategies that enable improved emptying of the bladder are of therapeutic interest.
Urinary incontinence is loss of bladder control leading to mild leaking all the way up to uncontrollable wetting. It results from weak sphincter muscles, overactive bladder muscles, damage to nerves that control the bladder from diseases such as multiple sclerosis and Parkinson's disease, and can occur after prostate surgery. As such, modulation strategies that treat urinary incontinence are of therapeutic interest.
Neurogenic bladder refers to bladder malfunction due to any type of neurological disorder, which can include stroke, multiple sclerosis, spinal cord injury, peripheral nerve lesions and numerous other conditions. Following a stroke, the brain often enters a cerebral shock phase, and the urinary bladder will be in retention (or detrusor areflexia). Around 25% of stroke patients develop acute urinary retention. Following the cerebral shock phase, the bladder often shows detrusor hyperreflexia, and the patient will have urinary frequency, urgency and urge incontinence. In multiple sclerosis, the most common urological dysfunction is detrusor hyperreflexia, occurring in as many as 50-90% of patients with MS. Detrusor areflexia is seen in 20-30% of patients, so treatment must be individualized based on urodynamic findings. In spinal cord injuries occurring from motor vehicle or diving accidents, an initial response of spinal shock is seen in which patients experience flaccid paralysis below the level of injury, and experiences urinary retention consistent with detrusor areflexia. Spinal shock phase lasts usually 6-12 weeks but may be prolonged. During this period, the urinary bladder often must be drained with either intermittent catheterization or an indwelling catheter. Following the spinal shock phase, bladder function returns, however with an increase in excitability, and results in detrusor hyperreflexia. Peripheral nerve lesions can be due to diabetes mellitus, herpes zoster, neurosyphilis, herniated lumbar disk disease, pelvic surgery and other conditions, and can result in detrusor areflexia. There is a continuing and unmet need for improved ability to impose beneficial control over behavior of end effectors. Embodiments of the present invention are variously directed to meeting such need.